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EGFR -mutated lung cancer is a significant subgroup of non-small cell lung cancer. To inhibit EGFR-mediated signals, multiple EGFR tyrosine kinase inhibitors (EGFR-TKI) have been developed; however, approximately one third of patients with EGFR -mutated lung cancer do not respond to EGFR-TKIs. More effective inhibition of EGFR-mediated signals is therefore necessary. For cancers expressing mutated EGFR , including EGFR T790M, which confers resistance to first- (gefitinib and erlotinib) and second- (afatinib) generation EGFR-TKIs, the synergistic efficacy of afatinib and cetuximab combination therapy has been reported in preclinical and clinical studies; however, the mechanisms underlying this effect remain elusive. In this study, we evaluated the effects of multiple EGFR-TKIs on the EGFR monomer-dimer equilibrium by inducing dimerization-impairing mutations in cells expressing EGFR Interestingly, we found that afatinib and dacomitinib exhibit a monomer preference: cells expressing dimerization-impaired EGFR mutants exhibited increased sensitivity to afatinib and dacomitinib relative to those with dimerization-competent EGFR mutants. Although EGFR-TKIs themselves induce dimerization of EGFR, the inhibition of dimerization by cetuximab overcame EGFR-TKI-induced dimerization. By shifting the monomer-dimer equilibrium toward monomer dominance using cetuximab, the effectiveness of afatinib and dacomitinib improved significantly. We report a novel and clinically relevant phenomenon, the monomer preference of EGFR-TKIs, which can explain the mechanism underlying the synergism observed in afatinib and cetuximab combination therapy. In addition, we propose the novel concept that monomer-dimer equilibrium is an important factor in determining EGFR-TKI efficacy. These findings provide novel insights into treatment strategies for EGFR-TKI-refractory non-small cell lung cancer.

Monomer Preference of EGFR Tyrosine Kinase Inhibitors Influences the Synergistic Efficacy of Combination Therapy with Cetuximab